This project examines the intermediate neural systems that mediate the gene-behavior relationships involv- ed in risk for development of substance use disorders (SUDs) with special focus on alcohol, cannabis, and nicotine. We will characterize this circuitry, study its interaction with two intermediate behavioral phenotypes (behavioral undercontrol and negative affectivity), and examine the contribution of selected genetic variants, and early-life stress on the neural correlates of impulsivity and negative emotionality in children with varying risk for development of SUDs in adulthood [G2 sample of the Michigan Longitudinal Study(MLS)]. We will examine these correlates during childhood and begin to characterize changes that occur during adolesc- ence. The general hypothesis is that dysregulation of the brain networks involved in processing and regula- tion of behavior and affect during childhood underlies a heightened predisposition to develop SUDs at a later age. Both behavioral undercontrol and affective dysregulation at an early age are strong predictors of SUDs later in life, and these processes are regulated by complex neuronal circuits. We will use fMRI to investigate these neural systems in a sample of 8-10 year old boys &girls (n=129) from the ongoing MLS in a longitud- inal design in which scanning occurs at 2-year intervals. It is expected that children at high risk for develop- ment of SUDs based on the risk conferred by behavioral phenotypes (measured initially as externalizing and internalizing behavior and later by developmental trajectory classes), will demonstrate alterations in the functional responses of neuronal circuitry involved in impulse control and emotional regulation. It is also ex- pected that this effect will be modified by genes and early-life stress. Changes in brain functional responses over time are expected to be influenced by risk conferred by genetic variants and early stress. As models of gene-trait-environment interaction over time are developed in the MLS, we will investigate the relationship between brain responses and these developmental phenotypes. As substance abuse problems develop in this sample, this information will be available during subsequent funding periods to determine dysfunctions in neural circuitry associated with the early development of SUDs during adolescence. RELEVANCE (See instructions): This project will provide in-depth understanding about the intermediate neural pathways underlying susceptibility to drug use disorders, their genetic basis, and the possible interactive role of the social environment in producing variations in risk over time. Findings will have direct implications for early identific- ation, prevention, and early treatment of at-risk individuals as well as those in early stages of drug addiction.